If ultimately approved, the soluble guanylate cyclase (sGC) stimulator riociguat would join three classes of drugs already cleared for use in PAH -- phosphodiesterase type 5 (PDE5) inhibitors, prostanoids, and endothelin-receptor antagonists -- and become the first pharmacologic therapy for CTEPH, for which the standard treatment is pulmonary endarterectomy.

In PATENT-1, patients received riociguat in two arms. Both groups were started at 1 mg three times daily, but in one group the dose was adjusted up to 2.5 mg three times daily and in the other the maximum dose was capped at 1.5 mg three times daily. The latter arm was considered exploratory.

In CHEST-1, riociguat was given starting at 1 mg three times daily, with adjustments up to 2.5 mg three times daily.

Adjustments in both trials were based on systolic systemic arterial blood pressure and the signs or symptoms of hypotension.

In the FDA review documents released before the meeting, however, the recommended dosing regimen for both PAH and CTEPH was to start at 0.5 mg three times daily and adjust the dose up to 1.5 mg three times daily. The rationale was that there wasn't an incremental benefit in terms of 6-minute walk distance when using doses higher than 1.5 mg three times daily but there was a greater risk of hypotensive events (systolic blood pressure less than 90 mm Hg).

One of the committee members, Stuart Rich, MD, of the University of Chicago, took issue with the FDA staff's position, however, saying that he was not concerned with hypotensive events defined solely on the basis of systemic blood pressure, but only with those events associated with symptoms.

Rich pointed out that there were indications that the 2.5-mg dose was superior to the 1.5-mg dose for other outcomes, including cardiac output, highlighting the need to make the higher dose available to increase flexibility for physicians.

"If the increased dose is associated with an increased cardiac output, that's a win as far as I'm concerned," he said.

"My plea to the agency is to let doctors be doctors. We have the ability in this patient population to decide what the optimal dose is," Rich said. That sentiment was echoed by most of the other panelists.

One concern Rich and some of the other committee members raised was the possibility that patients with CTEPH who would normally be eligible for surgery would forgo that option and take riociguat instead.

That's an issue, Rich said, because surgery has been shown to have such a large benefit -- and to be curative in some cases -- that patients should not be denied that option. He said he would like to see a program in place to ensure that patients are evaluated for operability before starting the drug.

The panelists also discussed whether a contraindication to concomitant use with nitrates -- as recommended on the proposed label -- was sufficient or whether a broader contraindication to use for patients with coronary disease who would likely need nitrates was warranted. The consensus was that the narrower contraindication was sufficient.

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University.

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